The invention relates to pyrimido[5,4-e][1,2,4]triazine-5,7-diamine compounds which are useful for inhibiting protein tyrosine phosphatases, particularly PTP1B.
Protein tyrosine phosphatases (PTPases) are key enzymes in the processes that regulate cell growth and differentiation. The inhibition of these enzymes can play a role in the modulation of multiple signaling pathways in which tyrosine phosphorylation dephosphorylation plays a role. PTP1B is a particular protein tyrosine phosphatase that is often used as a prototypical member of that class of enzymes.
PTPase inhibitors are recognized as potential therapeutic agents for the treatment of diabetes. See, e.g. Moeller et al., 3(5):527-40, Current Opinion in Drug Discovery and Development, 2000; or Zhang, Zhong-Yin, 5:416-23, Current Opinion in Chemical Biology, 2001.
It has been discovered that compounds of the formula: 
and the pharmaceutically acceptable salts thereof, wherein R1 and R2 are as defined below, inhibit protein tyrosine phosphatases, particularly PTP1B and so would be useful for lowering blood glucose concentrations in mammals.
As used in the specification, the term xe2x80x9clower alkylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain alkyl group containing a maximum of six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like. Lower alkyl groups may be unsubstituted or substituted by one or more groups selected independently from cycloalkyl, nitro, aryloxy, aryl, hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl and substituted amino. Examples of substituted lower alkyl groups include 2-hydroxyethyl, 3-oxobutyl, cyanomethyl and 2-nitropropyl.
The term xe2x80x9ccycloalkylxe2x80x9d means an unsubstituted or substituted 3- to 7-membered carbocyclic ring. Substituents useful in accordance with the present invention are hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkyl, aroyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, aryl, heteroaryl and substituted amino.
The term xe2x80x9clower alkoxyxe2x80x9d means a straight-chain or branched-chain alkoxy group containing a maximum of six carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.
The term xe2x80x9clower alkylthioxe2x80x9d means a lower alkyl group bonded through a divalent sulfur atom, for example, a methyl mercapto or a isopropyl mercapto group.
The term xe2x80x9carylxe2x80x9d means a mono- or bicyclic aromatic group, such as phenyl or naphthyl, which is unsubstituted or substituted by conventional substitutent groups. Preferred substituents are lower alkyl, lower alkoxy, hydroxy lower alkyl, hydroxy, hydroxyalkoxy, halogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano, nitro, perfluoroalkyl, alkanyoyl, aroyl, aryl alkynyl, lower alkynyl and lower alkanoylamino. The especially preferred substituents are lower alkyl, lower alkoxy, hydroxy, halogen, cyano and perfluoro lower alkyl. Examples of aryl groups that may be used in accordance with this invention are phenyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, m-hydroxy phenyl, m-methylthiophenyl, 2-methyl-5-nitrophenyl, 2,6-dichlorophenyl, 1-naphthyl and the like.
The term xe2x80x9clower alkyl-arylxe2x80x9d means a lower alkyl group as hereinbefore defined in which one or more hydrogen atoms is/are replaced by an aryl group as hereinbefore defined. Any conventional lower alkyl-aryl may be used in accordance with this invention, such as benzyl and the like.
The term xe2x80x9clower alkoxy-arylxe2x80x9d means a lower alkoxy group as hereinbefore defined in which one or more hydrogen atoms is/are replaced by an aryl group as hereinberfore defined. Any conventional lower alkoxy-aryl may be used in accordance with this invention, such as benzyloxy.
The term xe2x80x9clower alkoxycarbonylxe2x80x9d means a lower alkoxy group bonded via a carbonyl group. Examples of alkoxycarbonyl groups are ethoxycarbonyl and the like.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. The chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp: 196 and 1456-1457.
The present invention comprises compounds of the formula I: 
and the pharmaceutically acceptable salts thereof. In accordance with the invention,
R1 and R2 are individually selected from the group consisting of hydrogen, or
R1 and R2 together form a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Nxe2x80x94R3,
R3 is lower alkyl or xe2x80x94CH2xe2x80x94Ar, and
Ar is selected from the group consisting of unsubstituted phenyl; unsubstituted naphthyl; phenyl mono- or bi-substituted with lower alkyl, lower alkoxy, aryl, cycloalkyl, lower alkyl-aryl, lower alkoxy-aryl, lower alkyl-cycloalkyl, lower alkoxy-cycloalkyl, halo, cyano or trifluoromethyl; and naphthyl mono- or bi-substituted with lower alkyl, lower alkoxy, aryl, cycloalkyl, lower alkyl-aryl, lower alkoxy-aryl, lower alkyl-cycloalkyl, lower alkoxy-cylcoalkyl or halo.
Among the compounds of formula 1, preferred compounds are those of formula II: 
where Ar is selected from the group consisting of unsubstituted phenyl; unsubstituted naphthyl; phenyl mono- or bi-substituted with lower alkyl, lower alkoxy, aryl, cycloalkyl, lower alkyl-aryl, lower alkoxy-aryl, lower alkyl-cycloalkyl, lower alkoxy-cycloalkyl, halo, cyano or trifluoromethyl; and naphthyl mono- or bi-substituted with lower alkyl, lower alkoxy, aryl, cycloalkyl, lower alkyl-aryl, lower alkoxy-aryl, lower alkyl-cycloalkyl, lower alkoxy-cylcoalkyl or halo.
In one preferred embodiment of the compounds of formula II, Ar is unsubstituted phenyl or unsubstituted naphthyl.
In another preferred embodiment of the compounds of formula II, Ar is phenyl mono-substituted with lower alkyl, lower alkoxy, aryl, cycloalkyl, lower alkyl-aryl, lower alkoxy-aryl, halo, cyano or trifluoromethyl.
In yet another preferred embodiment of the compounds.of formula II, Ar is phenyl mono-substituted with lower alkyl, lower alkoxy, halo, cyano or trifluoromethyl.
In still another preferred embodiment of the compounds of formula II, Ar is phenyl bi-substituted with lower alkyl, lower alkoxy, halo or cyano.
In a further preferred embodiment of the compounds of formula II, Ar is naphthyl mono-substituted with lower alkyl, lower alkoxy, lower alkyl-aryl, lower alkoxy-aryl or halo.
In yet a further preferred embodiment of the compounds of formula II, Ar is naphthyl mono-substituted with lower alkyl, lower alkoxy or halo.
In still a further preferred embodiment of the compounds of formula II, Ar is naphthyl bi-substituted with lower alkyl, lower alkoxy or halo.
The compounds of the invention can exist as stereoisomers and diastereomers, all of which are encompassed within the scope of the present invention.
The compounds of the invention inhibit PTP1B in vitro and have been shown to lower blood glucose levels in vivo. Thus, the compounds of the present invention would be useful for the treatment of diabetes.
The compounds of the invention can be administered orally, rectally, or parentally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually, or as opthalmalogical preparations. Capsules, tablets, suspensions or solutions for oral administration, suppositories, injection solutions, eye drops, salves or spray solutions are examples of administration forms.
Intravenous, intramuscular, oral or inhalation administration are preferred forms of use. The dosages in which the compounds of the invention are administered in effective amount depends on the nature of the specific active ingredient, the age and requirements of the patient and the mode of administration. Dosages may be determined by any conventional means, e.g., by dose-limiting clinical trials. In general, dosages of about 0.1 to 100 mg/kg body weight per day are preferred, with dosages of 1-25 mg/kg per day being particularly preferred.
The invention further comprises pharmaceutical compositions which contain a pharmaceutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. Such compositions may be formulated by any conventional means. Tablets or granulates can contain a series of binders, fillers, carriers or diluents. Liquid compositions can be, for example, in the form of a sterile water-miscible solution. Capsules can contain a filler or thickener in addition to the active ingredient. Furthermore, flavor-improving additives as well as substances usually used as preserving, stabilizing, moisture-retaining and emulsifying agents as well as salts for varying the osmotic pressure, buffers and other additives can also be present.
The previously mentioned carrier materials and diluents can comprise any conventional pharmaceutically acceptable organic or inorganic substances, e.g., water, gelatine, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like.
Oral unit dosage forms, such as tablets and capsules, preferably contain from 25 mg to 1000 mg of a compound of the invention. The compounds of the invention may be prepared by any conventional means. A particular method is described in the following Schemes 1 through 3. 
The intermediate chloromethyl compound 3 is prepared from commercially available 2,4-diamino-2-mercaptopyrimidine hemisulfate 1 as outlined in Scheme 1. S-methylation of 1 (e.g., using sodium hydroxide and methyliodide) followed by nitrosylation under standard conditions (e.g., using sodium nitrate with acetic acid at about 50xc2x0 C.) provides the intermediate arylnitrosyl derivative 2. Displacement of the thiomethyl group of 2 with hydrazine in a suitable solvent such as dimethylformamide at room temperature followed by condensation with commercially available chloromethylacetaldehyde diethyl acetal under acidic conditions (e.g., HCI) with heating (e.g., about 85xc2x0 C.) affords the chloromethyl derivative 3. 
The chloromethyl derivative 3 may then be reacted with a variety of known amines in a suitable solvent such as ethanol with heating (e.g., at about 80-100xc2x0 C.) to provide the corresponding aminomethyl derivatives 4 as outlined in Scheme 2. For amines R4NR5 of Scheme 2, R4 is xe2x80x94CH2CH2R1 and R5 is xe2x80x94CH2CH2R2, and R1 and R2 are as previously defined. 
The piperazine derivative 5 (e.g., derivative 4 where R4 and R5 together form a xe2x80x94CH2CH2NHCH2CH2xe2x80x94 moiety) is prepared from chloromethyl derivative 3 and piperazine as outlined in Scheme 2. Alkylation of derivative 5 with a variety of known alkyl halides (e.g., R3Br or R3I, where R3 is defined above) is carried out in a suitable solvent such as dimethylformamide using a suitable base such as potassium carbonate at room temperature to provide the dialkylated piperazine derivatives 6 as outlined in Scheme 3.